Systemic hypertension in two patients with ASL deficiency: A result of nitric oxide deficiency?

doi:10.1016/j.ymgme.2009.06.006

Molecular Genetics and Metabolism

Volume 98, Issues 1–2, October 2009, Pages 195-197

https://doi.org/10.1016/j.ymgme.2009.06.006 Get rights and content

Abstract

Argininosuccinic aciduria (ASA) is an inborn error of ureagenesis which if untreated leads to hyperammonemia, accumulation of argininosuccinic acid and arginine depletion. The presence of high blood pressure in patients with ASA has been reported so far as transient in one newborn. We describe the first two patients, one child and one young adult, with ASA and persistent systemic hypertension. Extensive evaluation of both patients excluded secondary causes of systemic hypertension. The intriguing link between nitric oxide (NO) production and hypertension lead us to hypothesize that the deficiency of endogenously synthesized arginine caused by ASL deficiency is responsible for the increased blood pressure.

Introduction

Argininosuccinic aciduria (ASA) (MIM 207900) is a rare, autosomal recessive defect of urea cycle resulting from l-argininosuccinate lyase (ASL; EC 4.3.2.1) deficiency. The reported incidence of this disease is about one in 70,000 live births in the United States [1], and thus, it is the second most common heritable disorder of the urea cycle. Patients with this disorder typically develop in the newborn period or during infancy vomiting, lethargy, developmental delay, and hyperammonemia. The biochemical hallmarks of this disease are elevations of the amino acids argininosuccinic acid and citrulline and low levels of plasma l-arginine. Current treatment consists of a low-protein diet and l-arginine supplementation [2]. However, despite treatment, patients often exhibit intellectual impairment and delayed motor skills. These consequences are mainly due to hyperammonemia, although it has been suggested that at least some of them might be due to deficiency of urea cycle intermediates [3]. Hypertension which resolved with intravenous infusion of l-arginine has been reported in a newborn with ASA [4]. The effect of l-arginine on blood pressure was further suggested by a second infant, without ASA reported by the same authors, who was administered intravenously with l-arginine for pituitary function evaluation and developed a drop in blood pressure responsive to discontinuation of l-arginine infusion [4]. Indeed, it has been shown in normal children that l-arginine infused systemically can lower blood pressure [5]. It is logical to hypothesize that ASL deficiency with a consequent intracellular arginine deficiency leads to nitric oxide (NO) deficiency. Here we report two patients of 19 and 9 years of age, with early- and late-onset ASA, respectively, affected with systemic hypertension. The patients we described here further suggest the beneficial effects of NO donor and urea cycle intermediates on blood pressure in ASL deficiency.

Section snippets

Case reports

In the last 2 years 47 patients with a urea cycle disorders have been regularly seen for follow-up visits in the Metabolic Clinic of Baylor College of Medicine at Texas Children’s Hospital, Houston, TX. Of these 47 patients, 25 were affected with ornithine transcarbamylase (OTC) deficiency, 2 with carbamyl phosphate synthetase (CPS) deficiency, 5 with citrullinemia, 7 with ASA, and 8 with argininemia.

Among the OTC deficiency case, only one 68-year-old woman was found to have mild increase in

Discussion

The presence of high blood pressure in patients with ASA can be anticipated based on pathophysiological speculations. l-Arginine production, which is dramatically reduced in ASA, is an important vasodilator and its action is mediated through NO synthesized by endothelial cells from l-arginine [9]. Several studies have shown that NO plays a crucial role in the pathogenesis of hypertension [10], [11]. However, so far only one patient, who developed transient hypertension in the newborn period

Acknowledgments

The authors acknowledge the additional members of Texas Children’s Hospital Biochemical Genetics Clinic Physician Staff (Drs. V. Reid Sutton, Brett Graham, Marwan Shinawi, and Fernando Scaglia), clinic nurses (Kerri Lamance, Elizabeth Bernica) and dietician (Jocelyn Mills). The authors thank the clinical research staff (Mary Mullins, Susan Carter, and Alyssa Tran). The work was supported in part by the Baylor College of Medicine General Clinical Research Center (RR00188), Mental Retardation and

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Cited by (36)

Early allograft dysfunction in a pediatric liver allograft with an occult pathogenic mutation in the urea cycle
2023, American Journal of Transplantation
Liver transplantation risks transferring a genetic defect in metabolic pathways, including the urea cycle. We present a case of pediatric liver transplantation complicated by metabolic crisis and early allograft dysfunction (EAD) in a previously healthy unrelated deceased donor. Allograft function improved with supportive care, and retransplantation was avoided. Because hyperammonemia suggested an enzymatic defect in the allograft, genetic testing from donor-derived deoxyribonucleic acid revealed a heterozygous mutation in the ASL gene, which encodes the urea cycle enzyme argininosuccinate lyase. Homozygous ASL mutations precipitate metabolic crises during fasting or postoperative states, whereas heterozygous carriers retain sufficient enzyme activity and are asymptomatic. In the described case, postoperative ischemia/reperfusion injury created a metabolic demand that exceeded the enzymatic capacity of the allograft. To our knowledge, this is the first report of an acquired argininosuccinate lyase deficiency by liver transplantation and underscores the importance of considering occult metabolic variants in the allograft during EAD.
Nitric oxide deficiency is a primary driver of hypertension
2022, Biochemical Pharmacology
Citation Excerpt :
The purpose and objective of this technology is to provide an exogenous source of NO in patients that have endothelial dysfunction, hypertension, oral dysbiosis, use antiseptic mouthwash or proton pump inhibitors (PPIs). Hypertension has been anecdotally reported as a complication in human argininosuccinic aciduria (ASA) subjects [97,98]. It is known that ASA patients have decreased NO production but their vasodilatory response to NO donors is normal [99].
Hypertension remains a global health crisis. High blood pressure is the number one modifiable risk factor in the onset and progression of cardiovascular disease. Despite many different classes of drug therapies approved for hypertension, the use of polypharmacy and recommendations on lifestyle modification, many patients still suffer from uncontrolled or unmanaged hypertension. Nitric oxide is a naturally produced vasodilator that controls and regulates vascular tone and therefore controls and regulates blood pressure. Research over the past 40 years reveals that loss of nitric oxide production, termed endothelial dysfunction, is the earliest event in the development of hypertension. Strategies aimed at preventing the loss of nitric oxide production and/or therapeutic strategies designed to restore nitric oxide production will likely have a positive effect on patients’ health and lead to better management of blood pressure. This review article will focus on the loss of nitric oxide production as the primary contributor to hypertension and also discuss safe and clinically proven strategies to restore nitric oxide production and recapitulate nitric oxide based signaling in humans.
ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus
2019, Cell Reports
Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits. By generating LC-ASL-conditional knockout (cKO) mice, we further demonstrate altered response to stressful stimuli with increased seizure reactivity in LC-ASL-cKO mice. Depletion of ASL in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH) and to decreased catecholamines synthesis, due to decreased nitric oxide (NO) signaling. NO donors normalize catecholamine levels in the LC, seizure sensitivity, and the stress response in LC-ASL-cKO mice. Our data emphasize ASL importance for the metabolic regulation of LC function with translational relevance for ASL deficiency (ASLD) patients as well as for LC-related pathologies.
Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension
2018, American Journal of Human Genetics
Citation Excerpt :
Because of the large sample size used for model fitting, a t-value cutoff as ±1.96 was used to determine significance of the independent variables. First, we systematically assessed whether humans with ASLD have elevated blood pressures as this phenomenon has only been anecdotally reported.9,17–19 We had previously conducted the largest randomized controlled trial in ASLD (ClinVar: NCT00345605) where 12 individuals with ASLD (8 children and 4 adults) were enrolled in a crossover trial to assess the effects of a high dose (500 mg/kg/day) versus a low dose (100 mg/kg/day) of L-arginine on hepatic function tests10 (Table S1).
Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.
Quantitative amino acid analysis by liquid chromatography-tandem mass spectrometry: Implications for the diagnosis of argininosuccinic aciduria
2015, Clinica Chimica Acta
A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria
2012, Molecular Genetics and Metabolism
To compare the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high-dose arginine on liver function tests in patients with argininosuccinic aciduria (ASA).
Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100 mg·kg^− 1·d^− 1) combined with sodium phenylbutyrate (500 mg·kg^− 1·d^− 1) (LDA arm) or a high-dose of arginine alone (500 mg·kg^− 1·d^− 1) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol.
Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate (P < 0.03) and AST levels (P < 0.01) after treatment with high-dose arginine. In the subset of subjects with elevated AST or ALT, treatment with high-dose of arginine was associated with further increases in plasma levels of both aminotransferases. Whereas subjects had increased arginine and citrulline flux with high-dose arginine therapy, the glutamine flux was not different between the two treatment arms. The synthetic liver functions as assessed by prothrombin time, INR, and coagulation factor levels were not different between the HDA and LDA arms.
Administering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases.

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Systemic hypertension in two patients with ASL deficiency: A result of nitric oxide deficiency?

Abstract

Introduction

Section snippets

Case reports

Discussion

Acknowledgments

J. Pediatr.

Am. J. Hypertens.

J. Pediatr.

Newborn urine screening

Urea cycle enzymes

Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy

Pediatrics

Two cases suggesting a role for the l-arginine nitric oxide pathway in neonatal blood pressure regulation

Acta Paediatr.

In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

Proc. Natl. Acad. Sci. USA

Ambulatory blood pressure in schoolchildren

Arch. Dis. Child.

Vascular endothelial cells synthesize nitric oxide from l-arginine

Nature